Abstract Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is the biggest killer among infectious diseases. TB is also responsible for a quarter of all deaths associated with Antimicrobial Resistance (AMR). It is projected that by 2050, 75 million people, or one person every 12 seconds, will die due to AMR associated with TB. Long treatment times and increasing resistance to TB drugs have created the need to find new compounds with shorter treatment times and novel mechanisms of action. Triazolopyrimidine (TZP) compounds may lead to treatment shortening because they are effective against both replicating and non-replicating Mtb, and may address drug resistance because they target QcrB (ubiquinone cytochrome C oxidoreductase), a protein not currently targeted with existing TB drugs. During Phase I, we propose to optimize the physicochemical and ADME-PK properties of the TZP series and study the effects of this series in combination with other respiratory inhibitors such as bedaquiline. We will identify compounds with suitable potency, in vivo exposure, and tolerability. We will use an optimized compound to demonstrate efficacy in an animal model of TB infection and we will determine the kill kinetics and growth inhibition properties of the compounds alone and in combination with other respiratory inhibitors under replicating and non-replicating conditions. At the conclusion of these studies, we will have demonstrated feasibility that the TZP series, in combination with other respiratory inhibitors, results in treatment shortening. We will have completed a proof of concept animal study to demonstrate in vivo efficacy. During Phase II, we will complete lead optimization, further characterize the biological activity, and expand in vivo studies.